Many different forms of cancer exist, and it is believed that there are many different causes of the disease. The incidence of cancer varies, but it represents the second highest cause of mortality, after heart disease, in most developed countries. Current estimates suggest that one in three Americans alive at present will suffer from some form of cancer. There is a well-recognised need to develop new and improved therapies for treating cancers. Furthermore, there is also a requirement to develop therapeutic agents that could be used to inhibit the development of cancer in the general population, susceptible high-risk individuals or as an agent to prevent re-occurrence of disease in individuals already affected.
Human tumour viruses are recognised to be a major cause of human cancer, and there is a great deal of evidence which supports the contention that these viruses cause cancer by inducing genetic instability in infected cells. Indeed, both the human T-cell leukemia virus type 1 (HTLV1) Tax and the human papilloma virus type 16 (HPV16) E6 oncoproteins are known to induce genetic instability producing abnormal numbers of centrosomes, multinucleation and nuclear atypia.
One approach to the treatment of cancers caused by viruses is disclosed in International Publication No. WO2005/053694, which outlines the use of certain HIV protease inhibitors (which had previously been proposed for use as orally ingested medicaments for the systemic clinical management of retroviral infections such as HIV) as being clinically useful for topical administration to tissues to prevent or treat malignancies caused by human papilloma virus. The authors recognised that HIV protease inhibitors, such as indinavir, were useful for treating human papilloma virus (HPV) infections and particularly cancers associated with such infections. The work was based on the author's realisation that a chymotryptic activity of the proteasome may be the preferred target for treatment of HPV infections and it is known that Indinavir and related inhibitors can suppress the chymotryptic activity of the 26S proteasome. Thus it was speculated that indinavir and related compounds act to inhibit the chymotryptic activity of the proteasome and could thereby be useful for treating HPV infections and in particular HPV infections that lead to the development of cancer (e.g. in the cervix, mouth, anus, vagina and penis).
International Publication No. WO2005/053694 went on to contemplate that a number of HIV protease inhibitors could be used in the treatment of cancer (indinavir was identified as the most preferred) but also highlighted that certain HIV protease inhibitors (particularly ritonavir) did not appear to have the same activity as inhibitors such as indinavir. Indeed combinations of ritonavir and other protease inhibitors were actually shown to be less effective in this regard and therefore ritonavir fell outside the definition of the efficacious inhibitors contemplated in that specification.
A number of clinical trials for cancer have been conducted using ritonavir alone or ritonavir with lopinavir. However, each of these trials suggested the compounds would not be useful in the field of oncology. For instance, ritonavir has shown activity against pre-invasive cells derived from the cervix but was not effective against more advanced invasive cervical disease (Barillari, G., Iovane, A., Bacigalupo, I., Palladino, C., Bellino, S., Leone, P., Monini, P., Ensoli, B., Ritonavir or saquinavir impairs the invasion of cervical intraepithelial neoplasia cells via a reduction of MMP expression and activity. AIDS, 2012, 26(8):909-19.). This finding would potentially lead a skilled person to discount using ritonavir since elimination of early stage neoplastic cells (without being effective against advanced cells) could promote the evolution of more invasive forms of the disease. Another clinical trial with ritonavir (Laurent, N., de Boüard, S., Guillamo, J. S., Christov, C., Zini, R., Jouault, H., Andre, P., Lotteau, V., Peschanski, M. Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo. Mol Cancer Ther. 2004, 3(2):129-36) reported that ritonavir alone against glioma had no effect in vivo. A subsequent trial of ritonavir/lopinavir in humans had very little effect against glioma (Ahluwalia, M. S., Patton, C., Stevens, G., Tekautz, T., Angelov, L., Vogelbaum, M. A., Weil, R. J., Chao, S., Elson, P., Suh, J. H., Barnett, G. H., Peereboom, D. M., Phase II trial of ritonavir/lopinavir in patients with progressive or recurrent high-grade gliomas. J. Neurooncol. 2011, 102(2):317-21)
Infection with high-risk types of HPV has now been established as the main aetiological agent for invasive cervical cancer (ICC) and globally there are >270,000 deaths from this disease per annum with over 85% of these occurring in low resource countries. For example, in Kenya it is the most common cancer accounting for between 18-23% of all diagnosed cases of cancer.
The development of ICC can take 10-20 years and is preceded by HPV related pre-invasive pathology which is characterised as either low-grade (CIN1) or high-grade cervical intraepithelial neoplasia (CIN2/3). Lesions can be screened for by cervical cytology testing where they are diagnosed (or graded) as either borderline atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL).
The reduction in ICC related mortality in the developed world has been largely dependent on organised cytology screening and similar trends in cervical cancer mortality have been achieved by organised single screen and treatment in the third world. However, in the poorer nations lack of resources and health education means that most pre-invasive cervical disease remains undiagnosed and untreated. Thus, where resources are limited, low-cost screening and treatment options are clearly a high priority.
Current treatment options in clinical practice are either by ablative (destructive) or excisional modalities. Systematic reviews have demonstrated that these treatment modalities have similar success rates but have different morbidities. In the developed world, Large Loop Excision of the Transformation Zone LLETZ (aka loop electrosurgical excision procedure—LEEP) is used in the majority of colposcopy clinics. Over 80% of these procedures are performed under local analgesia and the whole of the transformation zone is available for subsequent histological examination. The procedure is associated with a risk of primary/secondary haemorrhage, prolonged discharge, infection and a risk of preterm delivery in subsequent pregnancies. The former side effects can be problematic particularly in low resource countries. Ablative treatment in the form of cold coagulation and cryotherapy are often advocated for use in these settings since these are low cost, require minimal infrastructure and can be carried out by trained non-medical health professionals. However, some studies have suggested that cryotherapy has a higher failure rate compared to other treatment modalities.
There are a variety of locally-applied, non-surgical approaches which have been evaluated for the treatment of cervical dysplasia including; photodynamic therapy (PDT); off-licence use of the anti cytomegalovirus (CMV) drug cidofovir; local application of the immune activator Imiquimod and direct application of the cytotoxic drug 5 flurouracil (5FU). Although some of these alternative treatment modalities show promise, their treatment outcomes are inferior to the reported 80-95% success rates obtained in quality assured colposcopy units.
An effective, inexpensive, non-surgical, self-applied treatment for HPV related cervical dysplasia would have great potential particularly in low resource settings. Furthermore, improved compliance with topical treatment would be enhanced, if the side effects are minimised.